Arylalkanoylamine derivative and drug containing the same

ABSTRACT

Arylalkanoylamine derivatives having excellent prolyl endopeptidase inhibitory action and resistances to hypoxia and amnesia which are represented by the following general formula (I): ##STR1## wherein A represents an indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl or benzofuranyl group; m represents an integer of 0 to 5; Z represents a hydroxymethyl, formyl, nitrile, hydroxyiminomethyl, semicarbazonomethyl or dialkoxymethyl group; X and Y may be the same or different, and individually represent a methylene group or sulfur atom, wherein compounds defined by the following substituents are excluded: A represents an indanyl, indenyl, or 1,2,3,4-tetrahydronaphthalenyl group; X and Y each represent a methylene group; and Z represents a hydroxymethyl or formyl group. Also disclosed is a pharmaceutical composition and method for improving mneme, cerebral circulation and cerebral metabolism comprising the arylalkanoylamine derivatives as the effective ingredient.

TECHNICAL FIELD

The present invention relates to a novel arylalkanoylamine derivativehaving a prolyl endopeptidase inhibitory action and resistances tohypoxia and amnesia, and a drug for improving mneme, cerebralcirculation and cerebral metabolism.

BACKGROUND ART

Senile dementia caused by such cerebral disorders as cerebrovasculardisorder, cerebral circulation disorder, cerebral metabolism disorderand memory disturbance has become a social problem in the society withprolonged life-span. Development of drugs useful for improving mneme,cerebral circulation and cerebral metabolism are thus desired. A recentclinical report [M. F. Mazurek et al., Neurology, 36, 1133(1986)]revealed a remarkable decrease of peptides participating in mneme orneurotransmission in brains of senile dementia patients.

Prolyl endopeptidase is an enzyme degrading peptides containing proline,and inactivates vasopressin, thyrotropin releasing hormone, neurotensinand the like, responsible for mneme and neurotransmission, which haspropagated mneme and learning tests on the inhibitors of the enzyme. Itis known that a compound inhibiting prolyl endopeptidase has resistanceto amnesia (Japanese Patent Unexamined Publication No. 62-201877;Japanese Pharmacological Journal, Minanisato, et al., 89, 323(1987);ibid, Taira, et al., 89, 243(1987)).

Drugs improving cerebral circulation, cerebral vasodilators, cerebralmetabolism accelerators, and the like are clinically used as drugs fortreating cerebrovascular disorders. These drugs, however, exhibit onlyinsufficient improvement in neurological symptoms or inability of dailylife in the patients, even though they are recognized to improvesubjective symptoms.

Therefore, a drug has been expected which has an action for improvingcerebral circulation and cerebral metabolism in combination with anaction for improving neurological disorders, such as resistance toamnesia and the like, and an action for improving disorders of movementsin daily life.

Thus, the present inventors have made various investigations forresearch of a compound having a prolyl endopeptidase inhibitory actionand an action of improving cerebral metabolism, and have synthesized animide derivative of amino acid, having resistance to amnesia. Theinventors have submitted a patent application (Japanese PatentUnexamined Publication No. 1-2503070). Further research works have beencontinued thereafter so as to make intensive investigations to generatea novel drug for improving mneme, cerebral circulation and brainmetabolism, which drug has an excellent prolyl endopeptidase inhibitoryaction in combination with an action for improving cerebral circulationand cerebral metabolism. Thus, the present invention has been achieved.

DISCLOSURE OF THE INVENTION

The present invention is to provide an arylalkanoylamine derivativerepresented by the following general formula (I): ##STR2## (wherein Arepresents an indanyl, indenyl group, 1,2,3,4-tetrahydronaphthalenyl orbenzofuranyl group; m represents an integer of 0 to 5; Z represents ahydroxymethyl, formyl, nitrile, hydroxyiminomethyl, semicarbazonomethylor dialkoxymethyl group; X and Y may be the same or different, andindividually represent methylene group or sulfur atom, provided that thecase wherein A represents an indanyl, indenyl, or1,2,3,4-tetrahydronaphthalenyl group; X and Y both represent a methylenegroup; Z represents a hydroxymethyl or formyl group, is excluded. Alsodisclosed is a pharmaceutical composition for improving mneme, cerebralcirculation and cerebral metabolism comprising the arylalkanoylaminederivate as an effective ingredient.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a view depicting the resistance to amnesia of the compound (I)of the present invention. The ordinate represents an amnesic ratio.

BEST MODE FOR CARRYING OUT THE INVENTION

In the general formula (I) representing the compound of the presentinvention, specific examples of indanyl group, indenyl group,1,2,3,4-tetrahydronaphthalenyl group and benzofuranyl group areillustrated by indan-1-yl group, indan-2-yl group, inden-1-yl group,inden-2-yl group, 1,2,3,4-tetrahydronaphthalen-1-yl group,1,2,3,4-tetrahydronaphthalen-2-yl group, benzofuran-2-yl group,benzofuran-3-yl group and the like. The dialkoxymethyl group as Zincludes dimethoxymethyl group, diethoxymethyl group and the like. Aninteger of 0 to 5, and preferably an integer of 0 to 3 in particular arerepresented by m.

The compound (I) of the present invention contains two or threeasymmetric carbons, and in accordance with the present invention, thesteric configuration of the substituents on the individual asymmetriccarbons may satisfactorily be either R or S or a mixture of R and S.

Representative examples of the compound (I) of the present invention areillustrated as follows.

1-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-L-prolinol

1-[3-(indan-2-ylacetyl)-L-thioprolyl]-L-prolinol

1-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-L-prolinol

1-[3-[4-(indan-2-yl)butanoyl]-L-thioprolyl]-L-prolinol

1-[3-[6-(indan-2-yl)hexanoyl]-L-thioprolyl]-L-prolinol

3-[1-(indan-2-ylcarbonyl)-L-prolyl]-L-prolinol

3-[1-(indan-2-ylacetyl)-L-prolyl]-L-thioprolinol

3-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-L-thioprolinol

3-[1-[4-(indan-2-yl)butanoyl]-L-prolyl]-L-thioprolinol

3-[1-[5-(indan-2-yl)pentanoyl]-L-prolyl]-L-thioprolinol

3-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-L-thioprolinol

3-[3-(indan-2-ylacetyl)-L-thioprolyl]-L-thioprolinol

3-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-L-thioprolinol

3-[3-[4-(indan-2-yl)butanoyl]-L-thioprolyl]-L-thioprolinol

3-[3-[6-(indan-2-yl)hexanoyl]-L-thioprolyl]-L-thioprolinol

1-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-L-prolinol

1-[3-(inden-2-ylacetyl)-L-thioprolyl]-L-prolinol

1-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-L-prolinol

1-[3-[4-(inden-2-yl)butanoyl]-L-thioprolyl]-L-prolinol

1-[3-[5-(inden-2-yl)pentanoyl]-L-thioprolyl]-L-prolinol

3-[1-(inden-2-ylcarbonyl)-L-prolyl]-L-thioprolinol

3-[1-(inden-2-ylacetyl)-L-prolyl]-L-thioprolinol

3-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-L-thioprolinol

3-[1-[4-(inden-2-yl)butanoyl]-L-prolyl]-L-thioprolinol

3-[1-[5-(inden-2-yl)pentanoyl]-L-prolyl]-L-thioprolinol

3-[1-[6-(inden-2-yl)hexanoyl]-L-prolyl]-L-thioprolinol

3-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-L-thioprolinol

3-[3-(inden-2-ylacetyl)-L-thioprolyl]-L-thioprolinol

3-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-L-thioprolinol

3-[3-[4-(inden-2-yl)butanoyl]-L-thioprolyl]-L-thioprolinol

3-[3-[5-(inden-2-yl)pentanoyl]-L-thioprolyl]-L-thioprolinol

1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-L-prolinol

1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-prolinol

1-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)pentanoyl]-L-thioprolyl]-L-prolinol

1-[3-[4-((S)-1,2,3,4-tetrahydronaphthalenyl-2-yl)butanoyl]-L-thioprolyl]-L-prolinol

1-[3-[5-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)pentanoyl]-L-thioprolyl]-L-prolinol

3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-L-thioprolinol

3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-L-thioprolinol

3-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-L-thioprolinol

3-[1-[4-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-prolyl]-L-thioprolinol

3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-L-thioprolinol

3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-thioprolinol

3-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-L-thioprolinol

3-[3-[4-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-thioprolyl]-L-thioprolinol

1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-L-prolinol

1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-prolinol

1-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-L-prolinol

1-[3-[4-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-thioprolyl]-L-prolinol

1-[3-[5-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)pentanoyl]-L-thioprolyl]-L-prolinol

3-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-L-thioprolinol

3-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-L-thioprolinol

3-[1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-L-thioprolinol

3-[1-[4-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-prolyl]-L-thioprolinol

3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-L-thioprolinol

3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-thioprolinol

3-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-L-thioprolinol

3-[3-[4-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-thioprolyl]-L-thioprolinol

3-[3-[6-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)hexanoyl]-L-thioprolyl]-L-thioprolinol

1-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-L-prolinol

1-[1-(benzofuran-2-ylacetyl)-L-prolyl]-L-prolinol

1-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-L-prolinol

1-[1-[4-(benzofuran-2-yl)butanoyl]-L-prolyl]-L-prolinol

1-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-L-prolinol

1-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-L-prolinol

1-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-L-prolinol

1-[3-[4-(benzofuran-2-yl)butanoyl]-L-thioprolyl]-L-prolinol

1-[3-[5-(benzofuran-2-yl)pentanoyl]-L-thioprolyl]-L-prolinol

3-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-L-thioprolinol

3-[1-(benzofuran-2-ylacetyl)-L-prolyl]-L-thioprolinol

3-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-L-thioprolinol

3-[1-[4-(benzofuran-2-yl)butanoyl]-L-prolyl]-L-thioprolinol

3-[1-[5-(benzofuran-2-yl)pentanoyl]-L-prolyl]-L-thioprolinol

3-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-L-thioprolinol

3-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-L-thioprolinol

3-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-L-thioprolinol

3-[3-[4-(benzofuran-2-yl)butanoyl]-L-thioprolyl]-L-thioprolinol

3-[3-[5-(benzofuran-2-yl)pentanoyl]-L-thioprolyl]-L-thioprolinol

1-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-L-prolinal

1-[3-(indan-2-ylacetyl)-L-thioprolyl]-L-prolinal

1-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-L-prolinal

1-[3-[4-(indan-2-yl)butanoyl]-L-thioprolyl]-L-prolinal

1-[3-[6-(indan-2-yl)hexanoyl]-L-thioprolyl]-L-prolinal

3-[1-(indan-2-ylcarbonyl)-L-prolyl]-L-thioprolinal

3-[1-(indan-2-ylacetyl)-L-prolyl]-L-thioprolinal

3-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-L-thioprolinal

3-[1-[4-(indan-2-yl)butanoyl]-L-prolyl]-L-thioprolinal

3-[1-[5-(indan-2-yl)pentanoyl]-L-prolyl]-L-thioprolinal

3-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-L-thioprolinal

3-[3-(indan-2-ylacetyl)-L-thioprolyl]-L-thioprolinal

3-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-L-thioprolinal

3-[3-[4-(indan-2-yl)butanoyl]-L-thioprolyl]-L-thioprolinal

3-[3-[6-(indan-2-yl)hexanoyl]-L-thioprolyl]-L-thioprolinal

1-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-L-prolinal

1-[3-(inden-2-ylacetyl)-L-thioprolyl]-L-prolinal

1-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-L-prolinal

1-[3-[4-(inden-2-yl)butanoyl]-L-thioprolyl]-L-prolinal

1-[3-[5-(inden-2-yl)pentanoyl]-L-thioprolyl]-L-prolinal

3-[1-(inden-2-ylcarbonyl)-L-prolyl]-L-thioprolinal

3-[1-(inden-2-ylacetyl)-L-prolyl]-L-thioprolinal

3-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-L-thioprolinal

3-[1-[4-(inden-2-yl)butanoyl]-L-prolyl]-L-thioprolinal

3-[1-[5-(inden-2-yl)pentanoyl]-L-prolyl]-L-thioprolinal

3-[1-[6-(inden-2-yl)hexanoyl]-L-prolyl]-L-thioprolinal

3-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-L-prolinal

3-[3-(inden-2-ylacetyl)-L-thioprolyl]-L-prolinal

3-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-L-prolinal

3-[3-[4-(inden-2-yl)butanoyl]-L-thioprolyl]-L-prolinal

3-[3-[5-(inden-2-yl)pentanoyl]-L-thioprolyl]-L-prolinal

1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-L-prolinal

1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-prolinal

1-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-L-prolinal

1-[3-[4-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-thioprolyl]-L-prolinal

1-[3-[5-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)pentanoyl]-L-thioprolyl]-L-prolinal

3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-L-thioprolinal

3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-L-thioprolinal

3-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-L-thioprolinal

3-[1-[4-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-prolyl]-L-thioprolinal

3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-L-thioprolinal

3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-thioprolinal

3-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-L-thioprolinal

3-[3-[4-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-thioprolyl]-L-thioprolinal

1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-L-prolinal

1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-prolinal

1-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-L-prolinal

1-[3-[4-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-thioprolyl]-L-prolinal

1-[3-[5-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)pentanoyl]-L-thioprolyl]-L-prolinal

3-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-propyl-L-thioprolinal

3-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-L-thioprolinal

3-[1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-L-thioprolinal

3-[1-[4-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-prolyl]-L-thioprolinal

3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-L-thioprolinal

3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-thioprolinal

3-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanol]-L-thioprolyl]-L-thioprolinal

3-[3-[4-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoyl]-L-thioprolyl]-L-thioprolinal

3-[3-[6-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)hexanoyl]-L-thioprolyl]-L-thioprolinal

1-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-L-prolinal

1-[1-(benzofuran-2-ylacetyl)-L-prolyl]-L-prolinal

1-[1-[3-(benzofuran-2-yl)propanoyl]-L-propyl]-L-prolinal

1-[1-[4-(benzofuran-2-yl)butanoyl]-L-propyl]-L-prolinal

1-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-L-prolinal

1-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-L-prolinal

1-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-L-prolinal

1-[3-[4-(benzofuran-2-yl)butanoyl]-L-thioprolyl]-L-prolinal

1-[3-[5-(benzofuran-2-yl)pentanoyl]-L-thioprolyl]-L-prolinal

3-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-L-prolinal

3-[1-(benzofuran-2-ylacetyl)-L-prolyl]-L-prolinal

3-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-L-prolinal

3-[1-[4-(benzofuran-2-yl)butanoyl]-L-prolyl]-L-prolinal

3-[1-[5-(benzofuran-2-yl)pentanoyl]-L-prolyl]-L-prolinal

3-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-L-thioprolinal

3-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-L-thioprolinal

3-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-L-thioprolinal

3-[3-[4-(benzofuran-2-yl)butanoyl]-L-thioprolyl]-L-thioprolinal

3-[3-[5-(benzofuran-2-yl)pentanoyl]-L-thioprolyl]-L-thioprolinal

(2S)-1-[1-(indan-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine aldoxime

(2S)-1-[1-(indan-2-ylacetyl)-L-prolyl]-2-pyrrolidine aldoxime

(2S)-1-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-2-pyrrolidine aldoxime

(2S)-1-[1-[4-(indan-2-yl)butanoyl]-L-prolyl]-2-pyrrolidine aldoxime

(4R)-3-[1-(indan-2-ylcarbonyl)-L-prolyl]-4-thiazolidine aldoxime

(4R)-3-[1-(indan-2-ylacetyl)-L-prolyl]-4-thiazolidine aldoxime

(4R)-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-4-thiazolidine aldoxime

(4R)-3-[1-[4-(indan-2-yl)butanoyl]-L-prolyl]-4-thiazolidine aldoxime

(2S)-1-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidine aldoxime

(2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine aldoxime

(2S)-1-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidine aldoxime

(2S)-1-[3-[3-(indan-2-yl)butanoyl]-L-thioprolyl-2-pyrrolidine aldoximealdoxime

(4R)-3-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidine aldoxime

(4R)-3-[3-(indan-2-ylacetyl)-L-thioprolyl]-4-thiazolidine aldoxime

(4R)-3-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinealdoxime

(4R)-3-[3-[4-(indan-2-yl)butanoyl]-L-thioprolyl]-4-thiazolidine aldoxime

(2S)-1-[1-(indan-2-ylcarbonyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-(indan-2-ylacetyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-[4-(indan-2-yl)butanoyl]-L-prolyl]-2-cyanopyrrolidine

(4R)-3-[1-(indan-2-ylcarbonyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-(indan-2-ylacetyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-[4-(indan-2-yl)butanoyl]-L-prolyl]-4-cyanothiazolidine

(2S)-1-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-[4-(indan-2-yl)butanoyl]-L-thioprolyl]-2-cyanopyrrolidine

(4R)-3-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-(indan-2-ylacetyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-[4-(indan-2-yl)butanoyl]-L-thioprolyl]-4-cyanothiazolidine

(2S)-1-[1-(indan-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[1-(indan-2-ylacetyl)-L-prolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(4R)-3-[1-(indan-2-ylcarbonyl)-L-prolyl]-4-thiazolidine carbaldehydedimethyl acetal

(4R)-3-[1-(indan-2-ylacetyl)-L-prolyl]-4-thiazolidine carbaldehydedimethyl acetal

(4R)-3-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidine carbaldehydedimethyl acetal

(4R)-3-[3-(indan-2-ylacetyl)-L-thioprolyl]-4-thiazolidine carbaldehydedimethyl acetal

(4R)-3-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[1-(indan-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[1-(indan-2-ylacetyl)-L-prolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-2-pyrrolidine carbaldehydediethyl acetal

(4R)-3-[1-(indan-2-ylcarbonyl)-L-prolyl]-4-thiazolidine carbaldehydediethyl acetal

(4R)-3-[1-(indan-2-ylacetyl)-L-prolyl]-4-thiazolidine carbaldehydediethyl acetal

(4R)-3-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(4R)-3-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidine carbaldehydediethyl acetal

(4R)-3-[3-(indan-2-ylacetyl)-L-thioprolyl]-4-thiazolidine carbaldehydediethyl acetal

(4R)-3-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[1-(indan-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[1-(indan-2-ylacetyl)-L-prolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-2-pyrrolidine carbaldehydesemicarbazone

(4R)-3-[1-(indan-2-ylcarbonyl)-L-prolyl]-4-thiazolidine carbaldehydesemicarbazone

(4R)-3-[1-(indan-2-ylacetyl)-L-prolyl]-4-thiazolidine carbaldehydesemicarbazone

(4R)-3-[1-[3-(indan-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde semicarbazone

(2S)-1-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(4R)-3-[3-(indan-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidine carbaldehydesemicarbazone

(4R)-3-[3-(indan-2-ylacetyl)-L-thioprolyl]-4-thiazolidine carbaldehydesemicarbazone

(4R)-3-[3-[3-(indan-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde semicarbazone

(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-2-pyrrolidinealdoxime

(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-2-pyrrolidinealdoxime

(2S)-1-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinealdoxime

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-4-thiazolidinealdoxime

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-4-thiazolidinealdoxime

(4R)-3-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-4-thiazolidinealdoxime

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidinealdoxime

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinealdoxime

(2S)-1-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinealdoxime

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidinealdoxime

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalene-2-ylacetyl)-L-thioprolyl]-4-thiazolidinealdoxime

(4R)-3-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinealdoxime

(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-2-cyanopyrrolidine

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-4-cyanothiazolidine

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-2-cyanopyrrolidine

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-4-cyanothiazolidine

(2S)-1-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-2-cyanopyrrolidine

(4R)-3-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-4-cyanothiazolidine

(2S)-1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-2-cyanopyrrolidine

(4R)-3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-4-cyanothiazolidine

(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-[3-((S)-1,2,3,4-tetrahydronaphthalene-2-ylpropanoyl]-L-thioprolyl]-2-pyrrolidine carbaldehyde dimethyl acetal

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(4R)-3-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(2S) -1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(2S)-1-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(2S)-1-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl-carbonyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-yl-carbonyl)-L-prolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(2S)-1-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(2S)-1-[1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylpropanoyl]-L-prolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(4R)-3-[1-((R)-1,2,3,4-tetrahydronaphthalene-2-ylcarbonyl)-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[1-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[1-[-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde diethyl acetal(2S)-1-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(2S)-1-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(4R)-3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[3-[3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-prolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(2S)-1-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen2-ylcarbonyl)-L-prolyl]-4-thiazolidine carbaldehyde semicarbazone

(4R)-3-[1-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-4-thiazolidinecarbaldehyde semicarbazone

(4R)-3-[1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-prolyl]-4-thiazolidine carbaldehyde semicarbazone

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(2S)-1-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde semicarbazone

(4R)-3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde semicarbazone

(4R)-3-[3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde semicarbazone

(2S)-1-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine aldoxime

(2S)-1-[1-(benzofuran-2-ylacetyl)-L-prolyl]-2-pyrrolidine aldoxime

(2S)-1-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinealdoxime

(4R)-3-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-4-thiazolidine aldoxime

(4R)-3-[1-(benzofuran-2-ylacetyl)-L-prolyl]-4-thiazolidine aldoxime

(4R)-3-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-4-thiazolidinealdoxime

(2S)-1-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidine aldoxime

(2S)-1-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine aldoxime

(2S)-1-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinealdoxime

(4R)-3-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidinealdoxime

(4R)-3-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-4-thiazolidine aldoxime

(4R)-3-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinealdoxime

(2S)-1-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-(benzofuran-2-ylacetyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-2-cyanopyrrolidine

(4R)-3-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-(benzofuran-2-ylacetyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-4-cyanothiazolidine

(2S)-1-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-2-cyanopyrrolidine

(4R)-3-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-4-cyanothiazolidine

(2S)-1-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[1-(benzofuran-2-ylacetyl)-L-prolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(4R)-3-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[1-(benzofuran-2-ylacetyl)-L-prolyl]-4-thiazolidine carbaldehydedimethyl acetal

(4R)-3-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[1-(benzofuran-2-ylacetyl)-L-prolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(4R)-3-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[1-(benzofuran-2-ylacetyl)-L-prolyl]-4-thiazolidine carbaldehydediethyl acetal

(4R)-3-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-2-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-2-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-2-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(4R)-3-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[1-(benzofuran-2-ylacetyl)-L-prolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(4R)-3-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-4-thiazolidinecarbaldehyde semicarbazone

(4R)-3-[1-(benzofuran-2-ylacetyl)-L-prolyl]-4-thiazolidine carbaldehydesemicarbazone

(4R)-3-[1-[3-(benzofuran-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde semicarbazone

(2S)-1-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(2S)-1-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(2S)-1-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(4R)-3-[3-(benzofuran-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde semicarbazone

(4R)-3-[3-(benzofuran-2-ylacetyl)-L-thioprolyl]-4-thiazolidinecarbaldehyde semicarbazone

(4R)-3-[3-[3-(benzofuran-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde semicarbazone

(2S)-1-[1-(inden-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine aldoxime

(2S)-1-[1-(inden-2-ylacetyl)-L-prolyl]-2-pyrrolidine aldoxime

(2S)-1-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-2-pyrrolidine aldoxime

(4R)-3-[1-(inden-2-ylcarbonyl)-L-prolyl]-4-thiazolidine aldoxime

(4R)-3-[1-(inden-2-ylacetyl)-L-prolyl]-4-thiazolidine aldoxime

(4R)-3-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-4-thiazolidine aldoxime

(2S)-1-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidine aldoxime

(2S)-1-[3-(inden-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine aldoxime

(2S)-1-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidine aldoxime

(4R)-3-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidine aldoxime

(4R)-3-[3-(inden-2-ylacetyl)-L-thioprolyl]-4-thiazolidine aldoxime

(4R)-3-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinealdoxime

(2S)-1-[1-(inden-2-ylcarbonyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-(inden-2-ylacetyl)-L-prolyl]-2-cyanopyrrolidine

(2S)-1-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-2-cyanopyrrolidine

(4R)-3-[1-(inden-2-ylcarbonyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-(inden-2-ylacetyl)-L-prolyl]-4-cyanothiazolidine

(4R)-3-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-4-cyanothiazolidine

(2S)-1-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-(inden-2-ylacetyl)-L-thioprolyl]-2-cyanopyrrolidine

(2S)-1-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-2-cyanopyrrolidine

(4R)-3-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-(inden-2-ylacetyl)-L-thioprolyl]-4-cyanothiazolidine

(4R)-3-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-4-cyanothiazolidine

(2S)-1-[1-(inden-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[1-(inden-2-ylacetyl)-L-prolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(4R)-3-[1-(inden-2-ylcarbonyl)-L-prolyl]-4-thiazolidine carbaldehydedimethyl acetal

(4R)-3-[1-(inden-2-ylacetyl)-L-prolyl]-4-thiazolidine carbaldehydedimethyl acetal

(4R)-3-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[3-(inden-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine carbaldehydedimethyl acetal

(2S)-1-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal

(4R)-3-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidine carbaldehydedimethyl acetal

(4R)-3-[3-(inden-2-ylacetyl)-L-thioprolyl]-4-thiazolidine carbaldehydedimethyl acetal

(4R)-3-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde dimethyl acetal

(2S)-1-[1-(inden-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[1-(inden-2-ylacetyl)-L-prolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[1-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(4R)-3-[1-(inden-2-ylcarbonyl)-L-prolyl]-4-thiazolidine carbaldehydediethyl acetal

(4R)-3-[1-(inden-2-ylacetyl)-L-prolyl]-4-thiazolidine carbaldehydediethyl acetal

(4R)-3-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[3-(inden-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine carbaldehydediethyl acetal

(2S)-1-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde diethyl acetal

(4R)-3-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidine carbaldehydediethyl acetal

(4R)-3-[3-(inden-2-ylacetyl)-L-thioprolyl]-4-thiazolidine carbaldehydediethyl acetal

(4R)-3-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde diethyl acetal

(2S)-1-[1-(inden-2-ylcarbonyl)-L-prolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[1-(inden-2-ylacetyl)-L-prolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-2-pyrrolidine carbaldehydesemicarbazone

(4R)-3-[1-(inden-2-ylcarbonyl)-L-prolyl]-4-thiazolidine carbaldehydesemicarbazone

(4R)-3-[1-(inden-2-ylacetyl)-L-prolyl]-4-thiazolidine carbaldehydesemicarbazone

(4R)-3-[1-[3-(inden-2-yl)propanoyl]-L-prolyl]-4-thiazolidinecarbaldehyde semicarbazone

(2S)-1-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[3-(inden-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine carbaldehydesemicarbazone

(2S)-1-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone

(4R)-3-[3-(inden-2-ylcarbonyl)-L-thioprolyl]-4-thiazolidine carbaldehydesemicarbazone

(4R)-3-[3-(inden-2-ylacetyl)-L-thioprolyl]-4-thiazolidine carbaldehydesemicarbazone

(4R)-3-[3-[3-(inden-2-yl)propanoyl]-L-thioprolyl]-4-thiazolidinecarbaldehyde semicarbazone

These compounds (I) of the present invention can be produced, forexample, by any of the methods (a), (b) and (c) described below.##STR3## (wherein B represents halogen atom, a lower alkoxy group orhydroxyl group; R1 represents hydrogen atom or a lower alkyl group; R2and D represent a lower alkyl group; A, m, X and Y represent the samemeaning as described above).

That is, a cyclic amino acid compound (III) reacts with an arylalkanederivative (II) to produce an N-substituted cyclic amino acid derivative(IV), with which a cyclic amino acid compound (V) reacts to obtain acompound (VI). The compound (Ia) of the present invention wherein Z ishydroxymethyl group can be obtained by subsequently reducing thecompound (VI). By further oxidation of the compound (Ia), the compound(Ib) of the present invention wherein Z is formyl group can be obtained.When hydroxylamine reacts with the compound (Ib), the compound (Ic) ofthe present invention wherein Z is hydroxyiminomethyl group can beobtained; When semicarbazide reacts with the compound (Ib), the compound(Id) of the present invention wherein Z is semicarbazonomethyl group canbe obtained; and when alcohol reacts with the compound (Ib), thecompound (Ie) of the present invention wherein Z is alkoxymethyl groupcan be obtained. When the compound (Ic) is dehydrated, the compound (If)of the present invention wherein Z is nitrile group can be obtained.

The reaction of the arylalkanoic acid derivative (II) with the cyclicamino acid compound (III) follows general reaction for generating acidamide. Of the arylalkanoic acid derivative (II), the one wherein B ishalogen atom or a lower alkoxy group is subjected to condensationreaction in the presence or absence of a base. When B is hydroxyl group,it is preferred to use carbodiimides as the condensation agent. Examplesof the base to be used in the reaction include an alkali metal hydroxideor carbonate, trialkyl amine, aromatic amine and the like; preferableexamples thereof are sodium hydroxide, potassium hydroxide and the like;preferable examples of carbodiimides include1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) or the hydrochloridesalt thereof (WSC.HCl), N, N'-dicylohexylcarbodiimide (DCC) and thelike. The reaction temperature is -20° to 200° C., and any solvent neverinvolved in such reaction may be satisfactory. Of the N-substitutedcyclic amino acid derivative (IV), the one wherein R1 is a lower alkylgroup can be hydrolyzed into carboxylic acid wherein R1 is hydrogenatom.

The reaction of the N-substituted amino acid derivative (IV) with thecyclic amino acid compound (V) is carried out following generalcondensation reaction. Such condensing agent if used may be any onegenerally employed, and preferably, the agent are carbodiimides such asWSC, WSC.HCl, DCC and the like. As the solvent, any solvent neverinvolved in the reaction may be satisfactory, preferably includingmethylene chloride, chloroform, tetrahydrofuran, dioxane and the like,and the reaction temperature is -20° to 80° C., preferably 0° to 40° C.Also, other condensation methods generally used, for example, acidchloride method, method with anhydrous mixed acids or the like, may besatisfactory (Fundamentals and Experimentals of Peptide Synthesis,Izumiya, et al., Maruzen (1985)).

The reduction of the compound (VI) may be done by general method byusing a reducing agent. As the reducing agent, preference is given tometal borohydrides such as sodium borohydride, lithium borohydride, zincborohydride, potassium borohydride and the like. As the solvent,preference is given to alcohols such as methanol, ethanol, propanol,isopropanol, butanol, t-butanol and the like and to ethers such astetrahydrofuran, dioxane and the like.

The oxidation of the compound (Ia) is done in the presence or absence ofan inactive organic solvent such as methylene chloride, chloroform,benzene and the like in a range of -80° to 100° C., by using as anoxidizing agent dimethyl sulfoxide, chromium trioxide-pyridine complex,t-butyl chromate, silver oxide, manganese dioxide and the like. Ifdimethyl sulfoxide is used as the oxidizing agent, it is preferred toeffect the oxidation in the co-presence of an activating agent such assulfur trioxide-pyridine complex, oxalyl chloride, DCC and the like.

The reaction of the compound (Ib) with hydroxyl amine or the saltthereof and the reaction of the compound (Ib) with semicarbazide or thesalt thereof are done in the presence or absence of a base according tothe general method.

The reaction of the compound (Ib) with alcohol is done in the presenceor absence of an acid catalyst according to the general method.

The dehydration of the compound (Ic) is done by general dehydrationreaction. For example, such dehydration is done in the absence ofsolvents or an inactive solvent such as benzene, chloroform, ether andthe like at room temperature or the reflux temperature, by using formicacid, acetic acid, acetic anhydride, phosphorous pentaoxide, thionylchloride and the like.

The compound (If) can be obtained also from the compound (Ib) withoutisolation of the compound (Ic). For example, the compound (Ib) andhydroxyl amine hydrochloride react together in an inactive solvent suchas dimethyl formamide and the like in the presence of a base such aspyridine and triethylamine, at room temperature to the refluxtemperature, followed by addition of selenium dioxide for dehydration,to prepare the compound (If). The compound (If) can be obtained by thedehydration of the corresponding amide, as well. ##STR4## (wherein R3represents the protective group of amino group; A, m, B, X, Y and Z arethe same meaning as described above.)

That is, the cyclic amine (VIII) reacts with the cyclic amino acidcompound (VII), and the protective group of the amino group of theresulting compound (IX) is eliminated to produce the compound (X),followed by the reaction with the arylalkanoic acid derivative (II) toobtain the compound (I) of the present invention.

The reaction of the cyclic amino acid compound (VII) with the cyclicamine (VIII) and the reaction of the compound (X) with the arylalkanoicacid derivative (II) are done in the same manner as described in theMethod (a). The elimination of the amino group of the compound (IX) canbe effected by general method.

By subjecting the resulting compound (Ia) of the present invention tothe reaction as described in the Method (a), the compounds (Ib), (Ic),(Id), (Ie) and (If) may be obtained. ##STR5## (wherein A, m, X, Y, Z andR1 represent the same meaning as described above.)

That is, the compound (I) of the present invention can be obtained bycondensing the N-substituted cyclic amino acid derivative (IV) with thecyclic amine (VIII). This condensation reaction may be done as in theMethod described above.

By subjecting the resulting compound (Ia) of the present invention tothe reaction as shown in the Method (a), the compounds (Ib), (Ic), (Id),(Ie) and (If) may be obtained.

If carbodiimides are herein used as a condensing agent in thecondensation reaction, a part of the resulting product may be subjectedto racemization in some cases. In such cases, it is preferred to employa method by mixed acid anhydride. For example, the reaction is effectedin an inactive solvent such as methylene chloride, chloroform, ether andthe like in the presence of a base such as triethylamine, pyridine,N-methylmorpholine and the like in a range of 0° to 50° C., by usingacid halides such as pivaloyl chloride, tosyl chloride and the like oracid derivatives such as ethyl chloroformate, isobutyl chloroformate andthe like.

The compound (I) of the present invention prepared by the mannerdiscussed above exhibits prolyl endopeptidase inhibitory activity,anti-hypoxic activity, and anti-amnesic activity at the same time, andis a highly safe compound. It is therefore useful as a drug forimproving mneme, cerebral circulation and cerebral metabolism.

Drugs for improving mneme, cerebral circulation and cerebral metabolismwith the effective compound being the compound (I) of the presentinvention may be prepared into formulations for oral or parenteraladministration, by compounding pharmaceutically acceptable additives. Incase of formulations for oral administration, the compound can beformulated into tablets, powders, granules and capsules, by appropriatecombinations thereof with excipients such as lactose, mannitol, cornstarch, crystalline cellulose and the like; binders such as cellulosederivatives, gum arabic, gelatin and the like; disintegrating agentssuch as carboxymethyl cellulose calcium and the like; and lubricantssuch as talc, magnesium stearate and the like. These solid formulationscan be prepared into enteric coated formulations, by using a coatingbase such as hydroxypropylmethyl cellulose terephthalate,hydroxypropylmethyl cellulose acetate succinate, cellulose acetatephthalate, methacrylate copolymer and the like. In case of formulationsfor parenteral administration, the compound can be formulated intoinjectable solutions by combination with, for example, water, ethanol,glycerin, routine surfactants and the like, and can be formulated intosuppositories by using a base for suppositories.

The dose of the compound (I) of the present invention varies dependingon the age, body weight, symptom, therapeutic effect, dosage, and periodfor administration, but generally the oral dose is in a range of 0.1 to2,000 mg/day, preferably 1 to 200 mg/day, which is preferably divided ina range of 1 to 3 for administration.

EXAMPLES

The present invention will now be described in details with reference toexamples, but the invention is not limited to them.

EXAMPLE 1

1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinol ##STR6##

3-(Indan-2-ylacetyl)-L-thioproline (4.40 g) and L-prolinol (1.53 g) weredissolved in 150 ml of methylene chloride, followed by addition of 2.90g of WSC-HCl under agitation while cooling in ice and subsequentagitation for-another 30 minutes at room temperature. The reactionsolution was washed sequentially in 5 HCl, saturated aqueous solution ofsodium bicarbonate, saturated aqueous sodium chloride solution, followedby drying over anhydrous magnesium sulfate. After distilling off thesolvent under reduced pressure, the residue was purified by columnchromatography to obtain 2.40 g of1-[3-(indan-2-yl-acetyl)-L-thioprolyl]-L-prolinol. Yield; 42%.

IR(neat)cm⁻¹ : 3400, 3000˜2800, 1640, 1420, 740 NMR (CDCl₃) δ ppm:1.60˜2.10(4H, m), 2.50˜2.70 (4H, m), 2.90˜3.40 (5H, m), 3.46˜4.20 (5H,m), 4.35˜4.85(3H, m), 5.00˜5.55(1H, m), 7.10˜7.25(4H, m)

EXAMPLE 2

1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinal ##STR7##

1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinol (590 mg) andtrimethylamine (1.32 ml) were dissolved in 1.50 ml of dimethylsulfoxide, followed by addition of 1.55 g of sulfur trioxide-pyridinecomplex dissolved in 2.25 ml of dimethyl sulfoxide at room temperatureunder agitation, which was then agitated for 15 minutes. The reactionsolution was placed in ice-cold water, followed by extraction withchloroform. The organic phase was washed sequentially in 5% HCl,saturated aqueous sodium bicarbonate solution, saturated aqueous sodiumchloride solution, followed by drying over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by column chromatography, to obtain 107 mg of 1-[3-(indan-2-ylacetyl)-L-thioprolyl]-L-prolinal. Yield; 18%.

IR(neat)cm⁻¹ : 3400, 3100˜2800, 1730, 1640, 1420, 750 NMR (CDCl₃) δ ppm:1.80˜2.20 (4H, m), 2.50˜3.40 (9H, m), 3.55˜4.10 (2H, m), 4.25˜4.65 (1H,m), 4.60 (2H, m), 5.00˜5.20 (1H, m), 7.10˜7.20 (4H, m), 9.40˜9.60(1H, m)

EXAMPLES 3 TO 12

Following the same method as in Examples 1 and 2, the compounds shown intable 1 were obtained.

EXAMPLE 3

3-[1-(Indan-2,ylacetyl)-L-prolyl]-L-thioprolinol

EXAMPLE 4

1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-prolinol

EXAMPLE 5

3-[3-((S)-1,2,3,4-tetrahydronaphthalen2-ylacetyl)-L-thioprolyl]-L-thioprolinol

EXAMPLE 6

1-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-L-prolinol

EXAMPLE 7

3-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-L-thioprolinol

EXAMPLE 8

3-[1-(indan-2-ylacetyl)-L-prolyl]-L-thioprolinal

EXAMPLE 9

1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-prolinal

EXAMPLE 10

3-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-thioprolinal

EXAMPLE 11

1-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-L-prolinal

EXAMPLE 12

3-[1-(benzofuran-2-ylcarbonyl)-L-prolyl]-L-thioprolinal

                                      TABLE 1                                     __________________________________________________________________________    Arylalkanoylamine Derivatives [Formula(I)]                                    Ex.                       Yield                                               No.                                                                              A         m X  Y  Z    (%) IR (cm.sup.-1)                                                                      NMR (δppm)                          __________________________________________________________________________        ##STR8## 1 CH.sub.2                                                                         S  CH.sub.2 OH                                                                        65  (KBr): 3360, 2900, 1630, 1420, 750                                                  (CDCl.sub.3): 1.80-2.25(5H, m),                                               2.38-2.71(4H, m), 2.81-2.97(2H, m),                                           3.11-3.28(3H, m), 3.46- 3.72(3H, m),                                          3.98-4.06(1H, m), 4.39(1H, d, J=                                              9Hz), 4.48-4.55(1H, m), 5.00(1H, d,                                           J=9Hz), 5.08 -5.13(1H, m),                                                    7.10-7.18(4H, m)                          4                                                                                 ##STR9## 1 S  CH.sub.2                                                                         CH.sub.2 OH                                                                        66  (KBr): 3400, 2910, 1625, 1410, 740                                                  (CDCl.sub.3): 1.43-2.20(6H, m),                                               2.30-2.61(4H, m), 2.82-4.40(10H, m),                                          4.43-4.90(3H, m), 4.92- 5.54(1H, m),                                          7.02-7.25(4H, m)                          5                                                                                 ##STR10##                                                                              1 S  S  CH.sub.2 OH                                                                        77  (KBr): 3400, 2910, 1630, 1410, 740                                                  (CDCl.sub.3): 1.43-1.60(1H, m),                                               1.95-2.10(1H, m), 2.32-2.60(4H, m),                                           2.79-3.42(7H, m), 3.64- 4.12(2H, m),                                          4.38-5.08(5H, m), 5.10-5.48(1H, m),                                           7.03-7.08(4H, m)                          6                                                                                 ##STR11##                                                                              0 CH.sub.2                                                                         CH.sub.2                                                                         CH.sub.2 OH                                                                        63  (KBr): 3420, 2950, 2860, 1620, 1420,                                                (CDCl.sub.3): 1.72-2.57(8H, m),                                               3.48-4.47(7H, m), 4.80-5.40(2H, m),                                           7.23-7.75(5H, m)                          7                                                                                 ##STR12##                                                                              0 CH.sub.2                                                                         S  CH.sub.2 OH                                                                        73  (KBr): 3400, 2850, 1620, 1560, 1420,                                                (CDCl.sub.3): 1.92-2.43(4H, m),                                               2.85-3.00(1H, m), 3.17-3.38(1H, m),                                           3.65-3.82(2H, m), 4.00- 4.33(2H, m),                                          4.40(1H, d, J=10Hz), 4.49-5.33 (4H,                                           m), 7.27-7.72(5H, m)                      8                                                                                 ##STR13##                                                                              1 CH.sub.2                                                                         S  CHO  25  (neat): 3350, 2900- 2800, 1725, 1610, 1420,                                    740  (CDCl.sub.3): 1.91-2.40(4H,m),                                                2.40-2.72(4H, m), 2.90-3.40(5H, m),                                           3.45-3.70(2H, m), 4.52- 4.80(2H, m),                                          5.00-5.21(2H, m), 7.14-7.30(4H, m),                                           9.52-9.70(1H, m)                          9                                                                                 ##STR14##                                                                              1 S  CH.sub.2                                                                         CHO  13  (KBr): 3430, 2920, 1725, 1635, 1410,                                                (CDCl.sub.3): 1.38-1.57(1H, m),                                               1.85-2.58(9H, m), 2.75-3.00(3H, m),                                           3.18-3.42(2H, m), 3.45- 4.07(2H, m),                                          4.57-4.78(3H, m), 5.03-5.22(1H, m),                                           6.98-7.17(4H, m), 9.40-9.61(1H, m)        10                                                                                ##STR15##                                                                              1 S  S  CHO  16  (KBr): 3430, 2920, 1730, 1635, 1410,                                                (CDCl.sub.3): 1.37-1.60(1H, m),                                               1.86-2.02(1H, m), 2.20-2.57(4H, m),                                           2.77-3.00(3H, m), 3.05- 3.47(4H, m),                                          4.47-4.80(4H, m), 4.95-5.55(2H, m),                                           6.93-7.15(4H, m), 9.45-9.60(1H, m)        11                                                                                ##STR16##                                                                              0 CH.sub.2                                                                         CH.sub.2                                                                         CHO  13  (KBr): 3450, 2960, 1730, 1645, 1620, 1420,                                    740   (CDCl.sub.3): 1.80- 2.45(8H, m),                                              3.45-4.23(4H, m), 4.45-4.95(2H, m),                                           7.20-7.67(5H, m), 9.50 (1H, s)            12                                                                                ##STR17##                                                                              0 CH.sub.2                                                                         S  CHO  26  (KBr): 3400, 2950, 1730, 1650, 1620, 1405,                                    740   (CDCl.sub.3): 1.86-2.47(4H, m),                                               3.05-3.63(2H, m), 3.77-4.25(2H, m),                                           4.45-5.45(4H, m), 7.20- 7.72(5H, m),                                          9.50-9.58(1H, m)                          __________________________________________________________________________

EXAMPLE 13

1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinol ##STR18##

3-(Indan-2-ylacetyl)-L-thioproline (11.7 g) and triethylamine (5.6 ml)were dissolved in 100 ml of methylene chloride, followed by dropwiseaddition of 4.95 g of pivaloyl chloride under agitation while cooling inice for 15 minutes. Subsequently, 4.05 g of L-prolinol and 5.6 ml oftriethylamine were added dropwise and stirred at room temperature foranother one hour. The reaction solution were washed in 1N HCl, saturatedaqueous solution of sodium bicarbonate and saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, followed bydistillation of the solvent under reduced pressure. The resultingresidue was purified by column chromatography to obtain 8.80 g of1-[3-(indan-2-ylacetyl)-L-thioprolyl]-L-prolinol. Yield; 59%.

IR(neat)cm⁻¹ : 3600˜3100, 3000˜2800, 1630, 1410, 740 NMR (CDCl₃) δ ppm:1.60˜2.12(4H, m), 2.52˜2.69 (4H, m), 2.90˜3.37 (5H, m), 3.44˜4.35 (5H,m), 4.40˜4.85 (3H, m), 5.07 & 5.41 (total 1H, each t, J=7 Hz), 7.10˜7.20(4H, m)

EXAMPLE 14

(2S)-1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine aldoxime##STR19##

1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinal (372 mg), hydroxylaminehydrochloride salt (76 mg) and pyridine (89 μl) were dissolved in 5 mlof dimethylformamide, and stirred at 70° C. for 1.5 hours. Afterconcentrating the reaction solution under reduced pressure, theresulting residue was dissolved in 30 ml of methylene chloride, washedby saturated aqueous sodium chloride solution, and dried over magnesiumsulfate, followed by distillation of the solvent under reduced pressure.The resulting residue was purified by column chromatography to obtain120 mg of (2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinealdoxime. Yield; 31%.

m.p. 146°˜147° C. IR(KBr) cm⁻¹ : 3250, 3000˜2800, 1635, 1405, 740 NMR(CDCl₃) δ ppm: 1.80˜2.30 (4H, m), 2.50˜2.68 (4H, m), 2.80˜4.00 (7H,m),4.46˜5.19(4H, m), 6.58˜7.54(1H, m), 7.10˜7.20(4H, m), 8.49˜9.48 (1H, m)

EXAMPLE 15

(2S)-1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-2-cyanopyrrolidine ##STR20##

1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinal (1.12 g), hydroxylaminehydrochloride salt (229 mg) and pyridine (266 μl) were dissolved in 10ml of dimethylformamide, and stirred at 70° C. for 1.5 hours to obtain(2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine aldoxime.Subsequently, 366 mg of selenium dioxide was added to the reactionsolution, followed by agitation at 70° C. for 3 hours. The residue ofselenium dioxide was filtered under aspiration, and the resultingfiltrate was concentrated under reduced pressure. The residue wasdissolved in 50 ml of methylene chloride, washed sequentially in 1Nhydrochloric acid, saturated aqueous sodium chloride solution, andsaturated aqueous sodium chloride solution, and dried over magnesiumsulfate, followed by distillation of the solvent under reduced pressure.The resulting residue was purified by column chromatography to obtain278 mg of(2S)-1-[3-(indan-2-yl-acetyl)-L-thioprolyl]-2-cyanopyrrolidine. Yield;25%.

m.p. 99°˜100° C. IR(KBr) cm⁻¹ : 3600˜3200, 3000˜2800, 2230, 1655, 1405NMR (CDCl₃) δ ppm: 2.10˜2.30(4H, m), 2.52˜2.68 (4H, m), 2.87˜2.97 (1H,m), 3.10˜3.35 (4H, m), 3.60˜3.70(1H, m), 3.85˜3.95 (1H, m), 4.60˜4.67(2H, m), 4.75˜4.85 (1H, m), 4.93 (1H, t, J=7Hz), 7.11˜7.20 (4H, m)

EXAMPLE 16

(2S)-1-[3-((S)-1,2,3,4-Tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone ##STR21##

1-[3-(S)-1,2,3,4-Tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-prolinal(1.02 g), semicarbazide hydrochloride (0.30 g) and sodium acetate (0.22g) were dissolved in 20 ml of 70% ethanol, and stirred at 80° C. for 10minutes. The reaction solution was concentrated under reduced pressure,and the residue solution was concentrated under was dissolved in ethylacetate, washed in water, dried over anhydrous magnesium sulfate,followed by distillation of the solvent under reduced pressure. Theresulting residue was purified by column chromatography to obtain 0.56 gof(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinecarbaldehyde semicarbazone. Yield; 48%.

m.p. 88°˜91° C. IR(KBr) cm⁻¹ : 3500˜2800, 1730˜1550, 1400, 740 NMR(CDCl₃) δ ppm: 1.40˜1.56(1H, m), 1.85˜2.10 (5H, m), 2.15˜2.55(4H, m),2.74˜3.00(3H, m), 3.02˜3.38(2H, m), 3.42˜3.93 (2H, m), 4.46˜4.73 (3H,m), 5.10(1H, t, J=7Hz), 5.40˜5.80(1H, b), 7.00˜7.15(4H, m), 9.41˜9.13(1H, m)

EXAMPLE 17

(2S)-1-[1-((S)-1,2,3,4-Tetrahydronaphthalen-2-ylacetyl)-L-proplyl]-2-pyrrolidinecarbaldehyde dimethyl acetal ##STR22##

1-[3-((S)-1,2,3,4-Tetrahydronaphthalene-2-ylacetyl)-L-prolyl]-L-prolinal(1.2 g) was dissolved in 10 ml of methanol, and stirred at roomtemperature for 10 minutes, followed by distillation of the solventunder reduced pressure. The resulting residue was crystallized in ethylacetate to obtain 1.0 g of(2S)-1-[1-((S)-1,2,3,4-tetrahydronaphthalene-2-yl-acetyl)-L-prolyl]-2-pyrrolidinecarbaldehyde dimethyl acetal. Yield; 76%.

m.p. 103°˜106° C. IR(KBr) cm⁻¹ : 3600˜3200, 3000˜2800, 1630, 1420, 750NMR (CDCl₃) δ ppm: 1.40˜1.55(1H, m), 1.80˜2.53 (13H, m), 2.72˜3. 00 (3H,m), 3.39 (3H, s), 3.43 (3H, s), 6.95˜7.10 (4H. m)

EXAMPLES 18-28

Following the same method as in Example 2, 13, 14 or 15, the compoundsshown in Table 2 were obtained.

The names of the individual compounds are as follows.

EXAMPLE 18

3-[1-(Indan-2-ylacetyl)-L-prolyl]-L-thioprolinol.

EXAMPLE 19

1-[3-((S)-1,2,3,4-Tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-prolinol

EXAMPLE 20

1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinal.

EXAMPLE 21

3-[1-(Indan-2-ylacetyl)-L-prolyl]-L-thioprolinal.

EXAMPLE 22

1-[3-((S)-1,2,3,4-Tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-L-prolinal(m.p. 103°˜104° C.).

EXAMPLE 23

(2S)-1-[1-(Indan-2-ylacetyl)-L-prolyl]-2-pyrrolidine aldoxime (m.p.144°˜145° C.).

EXAMPLE 24

(2S)-1-[1-((S)-1,2,3,4-Tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-2-pyprolidinealdoxime (m.p. 170°˜171° C.).

EXAMPLE 25

(2S)-1-[3-((S)-1,2,3,4-Tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinealdoxime (m.p. 184°˜186° C.).

EXAMPLE 26

(2S)-1-[1-(Indan-2-ylacetyl)-L-prolyl]-2-cyanopyrrolidine.

EXAMPLE 27

(2S)-1-[1-((S)-1,2,3,4-Tetrahydronaphthalen-2-ylacetyl)-L-prolyl]-2-cyanopyrrolidine(m.p. 100°˜101° C.).

EXAMPLE 28

(2S)-1-[3-((S)-1,2,3,4-Tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-cyanopyprolidine(m.p. 126°˜127° C.).

                                      TABLE 2                                     __________________________________________________________________________    Arylalkanoylamine Derivatives [Formula (I)]                                   Ex.                            Yield                                          No. A          m  X   Y  Z     (%) IR (cm.sup.-1)                                                                      NMR (δppm)                     __________________________________________________________________________    18                                                                                 ##STR23## 1  CH.sub.2                                                                          S  CH.sub.2 OH                                                                         42  (neat): 3600-3100 3000-2800 1620,                                             1420, 740                                                                           (CDCl.sub.3): 1.88-2.25(4H, m),                                               2.38-2.71(4H, m), 2.82-2.99(2H,                                               m), 3.11-3.27(3H,                                                             m), 3.46-4.05(4H, m),                                                         4.37-5.11(5H, m), 7.10-7.22(4H,                                               m)                                   19                                                                                 ##STR24## 1  S   CH.sub.2                                                                         CH.sub.2 OH                                                                         78  (neat): 3650-3100 3000-2800 1625,                                             1410, 740                                                                           (CDCl.sub.3): 1.43-2.10(6H, m),                                               2.30-2.55(4H, m), 2.80-4.40(10H,                                              m), 4.43-4.90(3H, m), 5.08 &                                                  5.42(total 1H, each t, J=7Hz),                                                7.02- 7.20(4H, m)                    20                                                                                 ##STR25## 1  S   CH.sub.2                                                                         CHO   65  (KBr): 3650-3100 3000-2800 1730, 1640,                                        410, 740                                                                            (CDCl.sub.3): 1.90-2.16(4H, m),                                               2.50-2.68(4H, m), 2.89-2.99(1H,                                               m), 3.11-3.44(4H,                                                             m), 3.57-3.65(1H, m),                                                         3.90-3.99(1H, m), 4.59- 4.66(3H,                                              m), 5.08(1H, t, J=7Hz),                                                       7.10-7.20 (4H, m), 9.52(1H, d,                                                J=1Hz)                               21                                                                                 ##STR26## 1  CH.sub.2                                                                          S  CHO   60  (KBr): 3650-3100 3000-2800 1730, 1630,                                        410, 740                                                                            (CDCl.sub.3): 1.90-2.30(4H, m),                                               2.39-2.70(4H, m), 2.89-3.00(1H,                                               m), 3.11-3.25(4H,                                                             m), 3.48-3.65(2H, m),                                                         4.53-4.74(2H, m), 4.98- 5.12(2H,                                              m), 7.09-7.19(4H, m), 9.48(1H,                                                s)                                   22                                                                                 ##STR27## 1  S   CH.sub.2                                                                         CHO   87  (KBr): 3000-2800 1725, 1640, 1410,                                                  (CDCl.sub.3): 1.40-1.57(1H, m),                                               1.85-2.20(5H, m), 2.30-2.56(4H,                                               m), 2.76-3.02(3H, m), 3.23(1H,                                                dd, J=8Hz, 11Hz), 3.39(1H, dd,                                                J= 8Hz, 11Hz), 3.50-3.72(1H, m),                                              3.90-4.02 (1H, m), 4.60-4.72(3H,                                              m), 5.11(1H, t, J= 8Hz),                                                      7.00-7.15(4H, m), 9.54(1H, d,                                                 J=2Hz)                               23                                                                                 ##STR28## 1  CH.sub.2                                                                          CH.sub.2                                                                         CHNOH 21  (KBr): 3600-3100 3000-2800 1620, 1430,                                        40    (CDCl.sub.3): 1.83-2.27(8H, m),                                               2.34-2.71(4H, m), 2.88-3.01(1H,                                               m), 3.07-3.22(2H,                                                             m), 3.44-3.97(4H, m),                                                         4.31-5.13(2H, m), 6.58- 7.59(1H,                                              m), 7.09-7.21(4H, m), 8.74-9.75                                               (1H, m)                              24                                                                                 ##STR29## 1  CH.sub.2                                                                          CH.sub.2                                                                         CHNOH 65  (KBr): 3300-3000 3000-2800 1630, 1420,                                        50    (CDCl.sub.3): 1.35-1.58(1H, m),                                               1.82-2.50(13H, m), 2.70-3.00(3H,                                              m), 3.41-3.99(4H,                                                             m), 4.35-5.15(2H, m),                                                         6.58-7.60(1H, m), 6.95- 7.10(4H,                                              m), 7.80-8.74(1H, m)                 25                                                                                 ##STR30## 1  S   CH.sub.2                                                                         CHNOH 53  (KBr): 3250, 3000-2900 1630, 1400,                                                  (CDCl.sub.3): 1.61-1.58(1H, m),                                               1.85-2.10(5H, m), 2.20-2.56(4H,                                               m), 2.73-3.05(3H,                                                             m), 3.08-3.45(2H, m),                                                         3.50-4.08(2H, m), 4.64- 4.76(2H,                                              m), 4.81-5.28(2H, m), 6.60-7.68                                               (1H, m), 7.00-7.15(4H, m),                                                    7.80-8.05(1H, b)                     26                                                                                 ##STR31## 1  CH.sub.2                                                                          CH.sub.2                                                                         CN    35  (neat): 3600-3200 3000-2800 1630,                                             1420, 740                                                                           (CDCl.sub.3): 1.86-2.31(8H, m),                                               2.38-2.70(4H, m), 2.88-2.98(1H,                                               m), 3.10-3.22(2H,                                                             m), 3.44-3.89(4H, m),                                                         4.57-4.61(1H, m), 4.82- 4.84(1H,                                              m), 7.09-7.18(4H, m)                 27                                                                                 ##STR32## 1  CH.sub.2                                                                          CH.sub.2                                                                         CN    31  (KBr): 3600-3300 3000-2800 2300, 1660,                                        625, 1410                                                                           (CDCl.sub.3): 1.43-1.54(1H, m),                                               1.88-2.53(13H, m), 2.80-2.96(3H,                                              m), 3.49-3.91(4H,                                                             m), 4.58-4.63(1H, m),                                                         4.80-4.83(1H, m), 7.03- 7.09(4H,                                              m)                                   28                                                                                 ##STR33## 1  S   CH.sub.2                                                                         CN    17  (KBr): 3100-2800 2450, 2230, 1650,                                            1410, 1210                                                                          (CDCl.sub.3): 1.40-1.54(1H m),                                                1.95-2.05(1H, m), 2.18-2.56(8H,                                               m), 2.80-2.98(3H, m), 3.22(1H,                                                dd, J=7Hz, 12Hz), 3.33(1H, dd,                                                J= 7Hz, 12Hz), 3.60-3.70(1H, m),                                              3.86-3.98 (1H, m), 4.67-4.70(2H,                                              m), 4.81-4.86(1H, m), 4.94(1H,                                                t, J=7Hz), 7.00-7.15(4H,             __________________________________________________________________________                                             m)                               

Test Example 1 (Inhibitory activity against prolyl endopeptidase frombrain)

A prolyl endopeptidase was prepared from canine brains according to themethod of Yoshimoto et al. [J. Blochem., 94, 325 (19830].

Following buffer solutions A and B were used for the measurement.

Buffer A: 20 mM Tris-HCl buffer (pH 7.0)

Buffer B: Buffer A containing 0.1% gelatin, 1 mM EDTA, 1 mM2-mercaptoethanol.

Dilution of the prolyl endopeptidase preparation with Buffer B to aconcentration of 0.4 units/ml was done, and the resulting solution wasdefined as enzyme solution. To 940 μl of Buffer A was added 50 μl of theenzyme solution, followed by incubating at 37° C. for 10 minutes, towhich was added 10 μl of a solution of a sample compound dissolved indimethyl sulfoxide, and stirred and mixed together, followed by stayingat 37° C. for ten minutes. To the mixture was added 100 μl ofcarbobenzoxyglycylprolyl p-nitroanilide dissolved in 40% dioxane to afinal concentration of 2.5 mM, for reaction at 37° C. for 10 minutes, towhich was added 100 μl of 50% acetic acid containing 10% Triton X-100,thereby terminating the reaction.

For controls, dimethyl sulfoxide was added at the same amount (10 μl)instead of the solution of the sample compound; for blind tests,dimethyl sulfoxide and Buffer B were added instead of a sample compoundand the enzyme solution, respectively, at the same amounts for effectingthe same procedure.

Absorbance at 410 nm was measured with a spectrophotometer, and thevalues obtained by subtracting the value from the blind test from theindividual values ware defined as enzyme activity.

The prolyl endopeptidase inhibition potency (IC₅₀ value) was determinedas the concentration (M) of an individual compound inhibiting 50% of theenzyme activity of the control. The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                              Inhibition Potency                                      Compounds             IC.sub.50 (M)                                           ______________________________________                                        Compound of Example 2  1.0 × 10.sup.-9                                  Compound of Example 8  1.2 × 10.sup.-9                                  Compound of Example 9  3.5 × 10.sup.-10                                 Compound of Example 10                                                                               1.4 × 10.sup.-9                                  Compound of Example 11                                                                               6.9 × 10.sup.-8                                  Compound of Example 25                                                                               1.6 × 10.sup.-8                                  Compound of Example 28                                                                               7.5 × 10.sup.-10                                 Aniracetam            >1.0 × 10.sup.-3                                  SUAM 1221.sup.a)       7.6 × 10.sup.-8                                  ______________________________________                                         .sup.a) Compound disclosed in Japanese Patent Unexamined Publication No.      62201877.                                                                

Test Example 2 (Anti-hypoxic activity)

Groups of ICR male mice (Charles River Co.), age 4 to 5 weeks, eachgroup consisting of 10 mice and each mouse having been fasted for 24hours, were used for the test. Mice were placed in a transparentdesiccator (diameter: 19 cm, height: 30 cm) made of synthetic resin andhaving 2 valves, one at the upper portion and the other at the lowerportion, for replacing the gas therein. A mixed gas containing 4% O₂ and96% N₂ was fed from the upper valve at a rate of 10 l/min to measure theperiod of time until respiratory arrest took place for each mouse. Thetime measured was taken as the survival time.

Each tested compound suspended in an solvent was intraperitoneallyadministered 30 minutes before the start of the mixed gas feeding. Agroup of mice to which only the solvent was intraperitoneallyadministered was used as a control.

The anti-hypoxic activity was determined according to the followingequation: ##EQU1##

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                                                   Anti-hypoxic                                                         Dose     Activity                                           Compounds         (mg/kg)  (%)                                                ______________________________________                                        Control           --       100                                                Compound of Example 2                                                                           100      120                                                Compound of Example 5                                                                           100      115                                                Compound of Example 6                                                                           100      128                                                Compound of Example 8                                                                           100      120                                                Compound of Example 9                                                                           100      123                                                Compound of Example 10                                                                          100      129                                                Aniracetam        100      115                                                ______________________________________                                    

As shown in Tables 3 and 4, the compounds (I) of the present inventionare superior to aniracetam and SUAM 1221 (the compound described inJapanese Patent Unexamined Publication No. 62-201877, in their prolylendopeptidase inhibitory activities against the prolyl endopeptidasefrom canine brain and anti-hypoxic activities.

Test Example 3 (Resistance to amnesia)

The action of the compound of the present invention on the inhibition ofprolonged memory retention via an amnesia-inducing agent cyclohexyimide.

Male ICR mice (Charles River, Co. Ltd.), aged 0 to 7 weeks, wereemployed for this test with a step-down passive avoidance system.

On day 1, the mice were placed on a rubber-made platform, for 5-minutelearning trial. Whenever the mice got down on the grid floor, 0.2-mAelectric shock was continuously given to the mice until the mice got onthe platform.

The administration of cyclohexyimide and a sample compound was doneimmediately after the termination of the learning trial. Cyclohexyimidewas dissolved in physiological saline and subcutaneously administered ata dose of 150 mg/kg, while the compound of the present invention(Example 22) was suspended in 10% gum arabic for parenteraladministration at a dose of 30 μg/kg.

Twenty-four hours after the learning trial, retention test wasperformed. The mice were again placed on the platform, and the potentialtime required until the mice got down from the platform was counted. Theratio of the amnesic mice with the potential time less than 100 secondsper dose group was calculated, and the results are shown in FIG. 1. Thesignificance was tested by χ2-test, by using a level of significance (p)obtained by the comparative results with a group with a dose ofcyclohexyimide+solvent (*p<0.05, **p<0.01).

As a result, the amnesic ratio of the group with the dosage ofcyclohexyimide alone was 71.4%, whereas the amnesic ratio of the groupwith the dosage of the compound of the present invention was 36.8%,which indicates that the compound of the present invention exhibitsgreat resistance to amnesia.

Test Example 4 (Toxicity test; Parenteral administration)

Ten ICR mice (Charles River, Co.), male, aged 4 to 5 weeks, wereemployed per group. The compounds of Examples 1, 5, 8 and 12 wereseparately suspended in 10% gum arabic, and then, they were individuallyadministered parenterally at a dose of 300 mg/kg for subsequentobservation for 7 days. As a result, no death was counted under theabove conditions.

Test Example 5 (Toxicity test; Oral administration)

Five male ICR mice (Charles River, Co.) of age 5 weeks, were employedper group. The compound of Example 22 was suspended in a solvent, whichwas then administered orally at a dose of 1,000 mg/kg for subsequentobservation for 7 days. As a result, no death was counted under theabove conditions.

Preparation Example 1

    ______________________________________                                        Compound of Example 5                                                                             50 g                                                      Lactose            315 g                                                      Corn starch        125 g                                                      Crystalline cellulose                                                                             25 g                                                      ______________________________________                                    

The above components were uniformly mixed together, to which was added200 ml of an aqueous 7.5% hydroxypropyl cellulose solution. Theresulting mixture was prepared into granule with an extrusiongranulator, by using a screen of a 0.5-mm diameter, which wereimmediately rounded with a marumerizor, followed by drying to preparegranules.

By means of a fluid-bed granulator, the dry granules were coated with1.9 kg of a film coating solution of the following composition toprepare enteric granules.

    ______________________________________                                        Composition of coating solution:                                              ______________________________________                                        Hydroxypropylmethyl cellulose phthalate                                                             5.0      (w/w) %                                        Stearic acid          0.25     (w/w) %                                        Methylene chloride    50.0     (w/w) %                                        Ethanol               44.75    (w/w) %                                        ______________________________________                                    

Preparation Example 2

    ______________________________________                                        Compound of Example 10                                                                              20 g                                                    Lactose               100 g                                                   Corn starch           36 g                                                    Crystalline cellulose 30 g                                                    Carboxymethyl cellulose calcium                                                                     10 g                                                    Magnesium stearate     4 g                                                    ______________________________________                                    

The components of the above composition were uniformly mixed together,to prepare tables, each of 200 mg, by means of a single-punch tabletmachine using a punch of a 7.5-mm diameter.

Next, the tablets were subjected to spray coating with a coatingsolution of the following composition, thereby providing 10-mg coatingper tablet, to prepare enteric film-coating tablets.

    ______________________________________                                        Composition of coating solution:                                              ______________________________________                                        Hydroxypropylmethyl cellulose phthalate                                                             8.0      (w/w) %                                        Glycerin fatty acid ester                                                                           0.4      (w/w) %                                        Methylene chloride    50.0     (w/w) %                                        White beewax          0.1                                                     Isopropanol           41.5     (w/                                            ______________________________________                                    

Industrial Applicability

Because the compound of the present invention has the prolylendopeptidase inhibitory action and the resistances to hypoxia andamnesia, the compound concurrently has both of the actions for improvingmneme and for improving cerebral circulation and cerebral metabolism,and also is of higher safety. Thus, the compound of the presentinvention is useful as therapeutic drugs for sequelae of brainhemorrhage, brain infarct, cerebral aorta sclerosis, subarachnoidhemorrhage, head injury, brain surgery, cerebrovascular dementia,Parkinson disease, Altzheimer disease, Peck disease, sequela of hypoxiatoxicity, alcoholic encephalopathia, and the like.

What is claimed is:
 1. An arylalkanoylamine derivative represented bythe following general formula (I): ##STR34## wherein A represents anindanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl or benzofuranyl group;m represents an integer of 0 to 5; Z represents a nitrile,hydroxyiminomethyl or semicarbazonomethyl group; X and Y may be the sameor different, and individually represent a methylene group or sulfuratom.
 2. The arylalkanoylamine derivative of claim 1 wherein Arepresents an indanyl or 1,2,3,4-tetrahydronaphthalenyl group; and Zrepresents a nitrile group.
 3. The arylalkanoylamine derivative selectedfrom the group consistingof(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-pyrrolidinealdoxime; and(2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-cyanopyrrolidine.4. The arylalkanoylamine derivative (2S)-1-[3-((S)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]-2-cyanopyrrolidine.5. A pharmaceutical composition for improving mneme, cerebralcirculation and cerebral metabolism comprising an effective amount ofthe arylalkanoylamine derivative of claim 1 and a pharmaceuticallyacceptable carrier.
 6. A pharmaceutical composition for improving mneme,cerebral circulation and cerebral metabolism comprising an effectiveamount of the arylalkanoylamine derivative of claim 2 and apharmaceutically acceptable carrier.
 7. A pharmaceutical composition forimproving mneme, cerebral circulation and cerebral metabolism comprisingan effective amount of the arylalkanoylamine derivative of claim 3 and apharmaceutically acceptable carrier.
 8. A pharmaceutical composition forimproving mneme, cerebral circulation and cerebral metabolism comprisingan effective amount of the arylalkanoylamine derivative of claim 4 and apharmaceutically acceptable carrier.
 9. A method for treating seniledementia comprising administering to a subject an effective amount ofthe pharmaceutical composition of claim
 5. 10. A method for treatingsenile dementia comprising administering to a subject an effectiveamount of the pharmaceutical composition of claim
 6. 11. A method fortreating senile dementia comprising administering to a subject aneffective amount of the pharmaceutical composition of claim
 7. 12. Amethod for treating senile dementia comprising administering to asubject an effective amount of the pharmaceutical composition of claim8.